Lipopolysaccharides (LPS) are macromolecular amphiphiles that comprise up to one third by weight of the outer membrane of the gram-negative bacteria. LPS plays a vital role in the barrier function of the outer membrane in addition to exhibiting a large number of potent immunopathalogical activities. We propose to use multinuclear NMR methods to elucidate the structure of these molecules in order to understand at the molecular level the factors responsible for the biological activities (endotoxic and immunogenic) of lipopolysaccharides. A detailed understanding of the structure, metal ion binding and membrane organization aspects of LPS is an essential prerequisite to understanding the molecular basis for the function of LPS in maintaining the integrity of the bacterial outer membrane, in the pathogenesis of gram negative bacteria and for all efforts to synthesize the minimal active subunit of the endotoxin. In conjunction with appropriate biological studies, the data obtained from the NMR studies proposed herein will lead to the rational design of immune response modifiers, including the development of effective and safe immunotherapeutic agents.